GLUCAGON and ITS METABOLIC EFFECTS

BY:Khuram Aziz

M.Phill BiochemistryScientist by IBC Life Sciences

Member of Pakistan Young Scientist Association

OUTLINE

• Glucose homeostasis• Sources of glucose• Glucagon• Metabolic effects• Stimulation of Glucagon• Physiological actions• Regulation• Mechanism of glucagon

3

Glucose Equilibrium – A Wonder !!• Normal Blood Glucose– Fasting state : 60 to 100 mg%– Postprandial : 100 to 140 mg %

• What keeps the blood glucose in such a narrow range?

• Why are we not becoming hypoglycemic when we fast?

• Why is our blood sugar not shooting up to very high levels after a rich meal ?

• What are the regulatory and counter regulatory hormones ?

Let us grasp some of the fascinating answers !!

Hormonal Regulation of Metabolism

• Balance between anabolism and catabolism depends on levels of insulin, glucagon, GH, thyroxine, and others

19-35

Insulin and Glucagon Secretion

• Normal fasting glucose level is 60–100 mg/dl– Insulin and glucagon

normally prevent levels from rising above 170mg/dl after meals or falling below 50mg/dl between meals

19-40

6

Glucose Homeostasis

-cells release Glucagon stimulate glycogen breakdown and gluconeogenesis

-cells release insulin stimulate glucose uptake by peripheral tissues

Lower Blood Glucose

Higher Blood Glucose

Food

Between meals

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Homeostasis of Glucose Counter Regulation Mechanisms

• A steady maintenance of blood glucose with in a narrow range• Fasting state and fed states – their effects on BG

• Rate of glucose appearance Ra

• Rate of disappearance Rd must be in balance

• Blood Glucose (BG) = Ra - Rd • Control systems

– Glucose Receptors, GLUT 1-14– Controlling Hormones, Insulin, Glucagon, Cortisol, Epinephrine etc.,– Insulin Signaling sequences, Glucagon signaling – Effector Cells – Muscles, Liver, Brain, Heart and Adipose tissue – Feedback loops

• Negative feedback• Positive feedback

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• Glucose is derived from 3 sources• Intestinal absorption of dietary carbohydrates• Glycogen breakdown in liver and in the kidney. • Only liver and kidney have glucose-6-phosphatase. • Liver stores 25-138 grams of glycogen, a 3 to 8 hour supply.• Gluconeogenesis, the formation of glucose from precursors • These include lactate and pyruvate, amino acids (alanine and

glutamine), and to a lesser degree, from glycerol

Sources of Glucose in to blood

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• Short fast– Utilizes free glucose (15-20%)– Break down of glycogen (75%)

• Overnight fast– Glycogen breakdown (75%)– Gluconeogenesis (25%)

• Prolonged fast– Only 10 grams or less of liver glycogen remains.– Gluconeogenesis becomes sole source of glucose – Muscle protein is degraded for amino acids.– Lipolysis generates ketones for additional fuel.

Fasting State

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• Glucagon

• GLP-1 (Glucagon Like Peptide -1)– The most potent known insulin Secretagogue– It is made in the intestine by alternative

processing of the same precursor• Intracellular actions

Counter Regulatory Hormones

We will discuss in detail

11

Responses to decreasing Glucose levels

Response Glycemic theshhold

Physiological effects

Role in counter regulation

↓ Insulin 80 - 85 mg%

↑ Ra (↓ Rd) Primary First Defense

↑ Glucagon 65 - 70 mg%

↑ RaPrimary

Second Defense

↑ Epinephrine 65 - 70 mg%

↑ Ra ↓

Rd

Critical Third Defense

↑ Cortisol, GH 65 - 70 mg%

↑ Ra ↓

Rd

Not Critical

↑ Food ingestion

50 - 55 mg%

↑ Exogenous

Glucose

< 50mg% no cognitive change

Glucagon

• It is a peptide hormone.• Consists of a single chain of 29 amino acids.• Secreted by alpha cells of pancreatic islets of

langerhans.• Its main action is on the liver.• It tends to increase the blood glucose level.• Known as hyperglycemic hormone.

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Stimulation of Glucagon secretion– Blood glucose < 70 mg/dL

– High levels of circulating amino acids

– Especially arginine and alanine

– Sympathetic and parasympathetic stimulation

– Catecholamines

– Cholecystokinin, Gastrin

– Glucocorticoids

Glucagon Secretion

14

• Metabolic Effects of Glucagon– Increases hepatic glycogenolysis – Increases gluconeogenesis– Increases amino acid transport– Increases fatty acid metabolism (ketogenesis)

Role of Glucagon

15

Metabolic Effects of Glucagon

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• Metabolic Effects of Glucagon– Increases hepatic glycogenolysis – Increases gluconeogenesis– Increases amino acid transport– Increases fatty acid metabolism (ketogenesis)

Role of Glucagon

Clinical Pearl

1. Glucagon is the treatment for hypoglycemia

2. Glucagon Kit – 1 mg s/c or IM or IV injection –

3. In 2 to 3 minutes recovery

Physiological actions

Physiological actions

Physiological actions

Physiological actions

INSULINGLUCOSE

Metabolism

ATP

ATP sensitiveK+ channel Voltage dependent

Ca+ channel

Cell

Glucokinase

Somatostatin inhibits glucagon and insulin secretion

• somatostatin secretion is increased by the following;.

1-increased blood glucose

2-increased amino acids

3-increased fatty acids

4- increased concentrations of several of the gastrointestinal hormones released from the upper gastrointestinal tract in response to food uptake

• In turn somatostatin has multiple inhibitory effects as follow:

1-acts locally within the islets of langerhans themselves to depress the secretion of both insulin and glucagon

2-decreases both secretion and absorption in the gastrointestinal tract

3-decrease the motility of the stomach ,duodenum, and gallbladder

Somatostatin

Regulation of glucagon secretion

- Increased blood glucose inhibits glucagon secretion :

- increase blood amino acids stimulate glucagon secretion :

High concentrations of amino acids as occur in the blood after protein meals stimulate the secretion of glucagon .this is the same effect that amino acids have in stimulating insulin secretion.

Thus in this instance the glucagon and insulin responses are not opposite.

- exercise stimulates glucagon secretion.

-exercise stimulates glucagon secretion :

In exhaustive exercise, the blood concentration of glucagon often increases fourfold to fivefold. A beneficial effect of the glucagon is that to prevents a decrease in blood glucose

One of the factors that might increase glucagon secretion in exercise is increased circulating amino acids .other factors such as beta –adrenergic stimulation of the islets of langerhans ,may also play a role .

Regulation of blood glucose

Mechanism of action

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cAMP and activation of PKA

cAMP

Glucagon orepinephrine

inactiveadenylylcyclase

inactiveactive protein kinase A

phosphorylase kinase

p

p glycogenphosphorylase

glycogen glucose-1-phosphate

Liver cell

amplification cascade

cAMP

activeATP

inactiveinactive

activeactive

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